Centre for Integrated Systems Biology and Medicine, School of Biomedical Sciences, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK.
J Physiol. 2010 Apr 15;588(Pt 8):1333-47. doi: 10.1113/jphysiol.2009.183699. Epub 2010 Feb 22.
We recently provided evidence suggesting a role for cytokine-mediated inhibition of Akt/Forkhead box O 1 (FOXO1) signalling in the induction of muscle atrophy and impairment of muscle carbohydrate oxidation during lipopolysaccharide (LPS)-induced endotoxaemia in rats. We hypothesized that a low-dose dexamethasone (Dex; anti-inflammatory agent) infusion during endotoxaemia would prevent the LPS-induced impairment of Akt/FOXO1 signalling, and therefore prevent the muscle atrophy and impairment of carbohydrate oxidation. Chronically instrumented Sprague-Dawley rats received a continuous intravenous infusion of LPS (15 microg kg(-1) h(-1)), Dex (12.5 microg kg(-1) h(-1)), Dex+LPS or saline for 24 h at 0.4 ml h(-1). LPS infusion caused haemodynamic changes consistent with a hyperdynamic circulation and induced increases in muscle tumour necrosis factor-alpha (TNF-alpha; 10-fold, P < 0.001), interleukin-6 (IL-6; 14-fold, P < 0.001) and metallothionein-1A (MT-1A; 187-fold, P < 0.001) mRNA expression. Dex co-administration abolished most of the haemodynamic effects of LPS and reduced the increase in muscle TNF-alpha, IL-6 and MT-1A by 51% (P < 0.01), 85% (P < 0.001) and 58% (P < 0.01), respectively. Dex infusion during endotoxaemia also prevented the LPS-induced 40% reduction in the muscle protein:DNA ratio and decrease in Akt phosphorylation, and partially prevented the reduction in FOXO1 phosphorylation. However, Dex did not prevent the LPS-mediated increase in muscle atrophy F-box (MAFbx) and muscle RING finger 1 (MuRF1) mRNA expression, but did significantly reduce the LPS-mediated increase in cathepsin-L mRNA expression and enzyme activity by 43% (P < 0.001) and 53% (P < 0.05), respectively. Furthermore, Dex suppressed LPS-induced pyruvate dehydrogenase kinase 4 (PDK4) mRNA upregulation by approximately 50% (P < 0.01), and prevented LPS-mediated muscle glycogen breakdown and lactate accumulation. Thus, low-dose Dex infusion during endotoxaemia prevented muscle atrophy and the impairment of carbohydrate oxidation, potentially through suppression of cytokine-mediated Akt/FOXO inhibition, and blunting of cathepsin-L-mediated lysosomal protein breakdown.
我们最近的研究结果表明，细胞因子介导的 Akt/Forkhead box O1 (FOXO1)信号通路抑制在脂多糖（LPS）诱导的内毒素血症大鼠的肌肉萎缩和糖氧化受损中起作用。我们假设，在 LPS 诱导的内毒素血症期间，给予小剂量地塞米松（Dex；抗炎药）输注可防止 LPS 诱导的 Akt/FOXO1 信号通路受损，从而防止肌肉萎缩和糖氧化受损。慢性仪器化 Sprague-Dawley 大鼠以 0.4 ml/h 的速度持续静脉输注 LPS（15 µg/kg/h）、地塞米松（12.5 µg/kg/h）、地塞米松+LPS 或生理盐水 24 小时。LPS 输注引起与高动力循环一致的血流动力学变化，并导致肌肉肿瘤坏死因子-α（TNF-α；10 倍，P < 0.001）、白细胞介素-6（IL-6；14 倍，P < 0.001）和金属硫蛋白-1A（MT-1A；187 倍，P < 0.001）mRNA 表达增加。地塞米松联合给药消除了 LPS 的大部分血流动力学作用，并使肌肉 TNF-α、IL-6 和 MT-1A 的增加分别减少了 51%（P < 0.01）、85%（P < 0.001）和 58%（P < 0.01）。LPS 诱导的肌肉蛋白：DNA 比值降低和 Akt 磷酸化减少，以及 FOXO1 磷酸化减少也被地塞米松在 LPS 诱导的内毒素血症中的输注所预防。然而，地塞米松并未预防 LPS 介导的肌肉萎缩 F 盒（MAFbx）和肌肉 RING 指蛋白 1（MuRF1）mRNA 表达的增加，但显著减少了 LPS 介导的组织蛋白酶-L mRNA 表达和酶活性分别增加 43%（P < 0.001）和 53%（P < 0.05）。此外，地塞米松抑制 LPS 诱导的丙酮酸脱氢酶激酶 4（PDK4）mRNA 上调约 50%（P < 0.01），并防止 LPS 介导的肌肉糖原分解和乳酸积累。因此，在内毒素血症期间给予小剂量地塞米松输注可预防肌肉萎缩和糖氧化受损，这可能是通过抑制细胞因子介导的 Akt/FOXO 抑制和减轻组织蛋白酶-L 介导的溶酶体蛋白降解来实现的。
